Pathological bone remodeling (coupled osteoclast and osteoblast activity) is a major cause of hearing loss in chronic otitis media, with and without cholesteatoma and in active lesions of otosclerosis. This proposal is directed toward an understanding of the mechanisms controlling these localized remodeling processes in the middle ear with the long range goal of preventing and reversing the hearing loss caused by these diseases. The control of osteoclast activity in these diseases has not been thoroughly investigated. In middle ear disease, local stimulatory signals must activate autocrine or paracrine factors which activate cellular events leading to osteoclastic resorption at that site. Furthermore, there is evidence that these localized processes within the middle ear may lead to cochlear damage. Aims of this proposal are: 1. Cellular and biochemical events leading to localized bone loss. Endochondral and intramembranous bone will be investigated uscg light microscopy, transmission electron microscopy and immunohistochemistry in our model of locally induced bone resorption in the pressurized middle ear of the gerbil. An understanding of factors leading to localized bone loss is important to develop rational interventions in the treatment of middle ear disorders caused by pathological bone remodeling. 2. Since is likely that local factor(s) are present in regions of bone remodeling, culture medium will be conditioned by infusing it into regions of bone remodeling within the pressurized middle ear. The conditioned medium will ben be evaluated for the presence of factors which may activate osteoclasts or attract monocytes. (Primary cultures of osteoclast-like cells and Boyden blind well chambers with monocytes will be used.) If a factor can be extracted, it will later be purified and characterized. These methods may also lead to less of a dependence on lie animals and a greater use of cell cultures. 3. The exact nature of factor(s) leading to localized bone resorption and remodeling are unknown. Of he many potential candidates for such a factor are the arachidonic acid metabolites (prostaglandins and leukotrines). Arachidonic acid metabolites and their inhibitors will be tested for their activity against osteoclastic activity in vivo and against isolated osteoclast-like cells. Histomorphometry and time-lapse cinematography will be used. 4. Cochlear hair cell loss occurs in animals which have active bone resorption occurring within the middle ear. Cochlear damage (to hair cells, nerve fibers and the stria vascularis) will be studied in areas adjacent to localized bone loss and remodeling. The long-term objective of this study is to determine if factors produced in the remodeling process are toxic to the inner ear. If such factors exist, their identification may allow the prevention of cochlear hearing loss due to cholesteatoma and chronic otitis.